Rilmenidine is one of the lead compounds of the second generation of centrally acting antihypertensive drugs. In the first part of this study, 2 routes of administration of chronic treatment (1 month) with rilmenidine were compared. In conscious and pentobarbital-anesthetized spontaneously hypertensive rats (SHR), rilmenidine was delivered intraperitoneally either 250 μg/kg b.i.d. or 500 μg/kg/d infusion by means of minipumps. The possibility of rilmenidine-induced desensitization of central (brain cortex) and/or peripheral (kidney) α2-adrenoreceptors was studied in saturation experiments with the classic α2-adrenergic antagonist [3H]rauwolscine. In the second part of this study, the cardiovascular and cardiac antihypertrophic effects of the most efficient procedure were investigated.
The discontinuous administration of the drug was more effective than infusion. In rats treated with rilmenidine b.i.d., mean blood pressure was reduced by nearly 15% when no reduction occurred in SHRs treated with minipumps. With the first schedule of administration, plasma concentration of the drug reached a maximum of approximately 30 ng/ml when it was only 12 ng/ml with the continuous infusion of the same dose. Anesthesia with pentobarbital potentiated the antihypertensive effect of rilmenidine in rats treated discontinuously and unmasked an antihypertensive action in rats receiving the drug with minipumps. In saturation binding experiments, no significant changes in adrenergic receptors were observed in kidney membrane preparations. In contrast, in brain cortical membranes a reduction by about 50% of the Bmax of [3H]rauwolscine value was observed in rats treated discontinuously with rilmenidine. In contrast, a 400% increase of the Bmax was observed in the brain of rats treated with minipumps.
Over the one-month period of the second study, the discontinuous treatment with the 500 μg/kg/d dose of rilmenidine was still able to reduce blood pressure, at least at the peak concentration time, but did not induce any significant reduction of the ventricular mass. In conclusion, rilmenidine has only weak antihypertensive effects in conscious SHRs, even at doses higher than those that are active in rabbits and humans. As a consequence, it lacks significant cardiac antihypertrophic effects in this species. Pharmacokinetic data show that the rapid plasma withdrawal of this drug may explain this particular feature in rats.
Rilmenidine is a centrally acting antihypertensive drug, widely used to treat essential hypertension at low doses (15 to 30 μg/kg/d). Surprisingly, in literature, we found conflicting data about hypotensive effects of rilmenidine in spontaneously hypertensive rats (SHRs)—the most widely used model of experimental hypertension. This is especially the case when the effects of rilmenidine are observed in conscious animals. As a matter of fact, rilmenidine has been shown to markedly reduce blood pressure when injected intracerebroventricularly or intravenously in pentobarbital-anesthetized SHRs. In contrast, the administration of rilmenidine in conscious rats caused only very weak blood pressure effects. 1 So, in attempts to induce significant antihypertensive effects, many authors increased the doses of rilmenidine up to 1 mg/kg2 or 3 mg/kg3. Rilmenidine was even given at very high doses in chronic treatments with different procedures of administration: 6 mg/kg/d in drinking water during 12 days 4; 2 to 6 mg/kg/d via oral gavage during 3 and 6 days 5, or 5 to 15 mg/kg/d with subcutaneous osmotic minipumps during 14 days. 6
The present work was designed to discover a procedure in which the administration of a moderate dose of rilmenidine could reduce blood pressure in conscious SHRs. In the first part of this work, 2 modalities of rilmenidine (500 μg/kg/d) delivery were compared: a continuous infusion with intraperitoneal osmotic minipumps and a discontinuous administration with 2 intraperitoneal injections per day. In parallel to cardiovascular actions and to explore the possible causes of different responses between the 2 procedures, we tested 2 aspects: (i) a possible desensitization of central (brain cortex) and/or peripheral (kidney) α2-adrenergic receptors in binding experiments and (ii) a variation of the elimination kinetics of this compound in the course of time by plasma dosage.
In the second part of this work, the most efficient drug delivery procedure was used to investigate in detail the hemodynamic effects and the kinetics of chronically administered rilmenidine. Moreover, as the presence of myocardial imidazoline receptors has recently been described, 7 we investigated if cardiac anti-remodeling effects of this drug could be observed irrespective of any significant blood pressure-decreasing effect.
This work is the first pharmacodynamic/pharmacokinetic study in SHRs that could constitute a basis for future development of new centrally acting sympathoinhibitors derived from rilmenidine.